This project presents a multiscale computational investigation into stages of the infection process for two classes of viruses. We will study non-enveloped viruses to understand the mechanisms of membrane disruption by this class of virus. The ability of viruses to transport across membranes is essential for infection, yet for non-enveloped viruses the membrane disruption/transport mechanisms are poorly characterized. Non- enveloped viruses include many public health threats such as hepatitis A, hepatitis E, rotavirus, coxsackie B and rhinoviruses, which infect millions of people annually. The studies in the proposal will focus on two model system viruses, which infect insects, but the knowledge gained in these studies should be transferrable to human infecting non-enveloped viruses. Specifically, this proposal is concerned with understanding how lytic peptides are externalized from the interior of non-enveloped virus capsids and how the process is regulated by pH. Additionally, this study will focus on the interactions of the lytic peptides once they have been externalized from the capsid. These interactions include membrane binding, membrane insertion, peptide oligomerization and modulation of membrane mechanical properties. Significant findings from these studies will include detailed structural and energetic information regarding these infection related processes, which will be valuable in the development of anti-viral therapies against non-enveloped viruses. The second class of virus under study in this proposal are Arenaviruses, and specifically Lassa virus. Lassa virus causes hemorrhagic fevers in infected individuals and has high mortality rates. NIH classifies Lassa as a Category A Priority Pathogen because of the high risk it poses to public health and national security. This proposal is concerned with understanding the mechanisms of recognition of viral RNA by the Lassa nucleoprotein and the formation of the ribonucleoprotein complex, which is essential for viral replication and transcription. Characterizing the strength and nature of these interactions will provide the mechanistic basis for development of novel antiviral strategies targeted against Lassa. In all aspects of this proposal we will employ multiscale modeling methods and novel experimental data will be integrated with the computational studies through multiple experimental collaborations.